Single-cell RNA sequencing has transformed the study of biological tissues by enabling transcriptomic characterizations of their constituent cell states. Computational methods for gene expression deconvolution use this information to infer the cell composition of related tissues profiled at the bulk level. However, current deconvolution methods are restricted to discrete cell types and have limited power to make inferences about continuous cellular processes such as cell differentiation or immune cell activation.
View Article and Find Full Text PDFDespite a high response rate in chimeric antigen receptor (CAR) T cell therapy for acute lymphocytic leukaemia (ALL), approximately 50% of patients relapse within the first year, representing an urgent question to address in the next stage of cellular immunotherapy. Here, to investigate the molecular determinants of ultralong CAR T cell persistence, we obtained a single-cell multi-omics atlas from 695,819 pre-infusion CAR T cells at the basal level or after CAR-specific stimulation from 82 paediatric patients with ALL enrolled in the first two CAR T ALL clinical trials and 6 healthy donors. We identified that elevated type 2 functionality in CAR T infusion products is significantly associated with patients maintaining a median B cell aplasia duration of 8.
View Article and Find Full Text PDFHigh-resolution imaging has revolutionized the study of single cells in their spatial context. However, summarizing the great diversity of complex cell shapes found in tissues and inferring associations with other single-cell data remains a challenge. Here, we present CAJAL, a general computational framework for the analysis and integration of single-cell morphological data.
View Article and Find Full Text PDFSingle-cell RNA-sequencing has transformed the study of biological tissues by enabling transcriptomic characterizations of their constituent cell states. Computational methods for gene expression deconvolution use this information to infer the cell composition of related tissues profiled at the bulk level. However, current deconvolution methods are restricted to discrete cell types and have limited power to make inferences about continuous cellular processes like cell differentiation or immune cell activation.
View Article and Find Full Text PDFThe thalamus is the principal information hub of the vertebrate brain, with essential roles in sensory and motor information processing, attention, and memory. The complex array of thalamic nuclei develops from a restricted pool of neural progenitors. We apply longitudinal single-cell RNA sequencing and regional abrogation of Sonic hedgehog (Shh) to map the developmental trajectories of thalamic progenitors, intermediate progenitors, and post-mitotic neurons as they coalesce into distinct thalamic nuclei.
View Article and Find Full Text PDFPediatric ependymoma is a devastating brain cancer marked by its relapsing pattern and lack of effective chemotherapies. This shortage of treatments is due to limited knowledge about ependymoma tumorigenic mechanisms. By means of single-nucleus chromatin accessibility and gene expression profiling of posterior fossa primary tumors and distal metastases, we reveal key transcription factors and enhancers associated with the differentiation of ependymoma tumor cells into tumor-derived cell lineages and their transition into a mesenchymal-like state.
View Article and Find Full Text PDFA notable number of acute lymphoblastic leukemia (ALL) patients develop CD19-positive relapse within 1 year after receiving chimeric antigen receptor (CAR) T cell therapy. It remains unclear if the long-term response is associated with the characteristics of CAR T cells in infusion products, hindering the identification of biomarkers to predict therapeutic outcomes. Here, we present 101,326 single-cell transcriptomes and surface protein landscape from the infusion products of 12 ALL patients.
View Article and Find Full Text PDFBackground: Autologous T cells engineered to express a chimeric antigen receptor (CAR) specific for CD19 molecule have transformed the therapeutic landscape in patients with highly refractory leukemia and lymphoma, and the use of donor-generated allogeneic CAR T is paving the way for further breakthroughs in the treatment of cancer. However, it remains unknown how the intrinsic heterogeneities of these engineered cells mediate therapeutic efficacy and whether allogeneic products match the effectiveness of autologous therapies.
Methods: Using single-cell mRNA sequencing in conjunction with CITE-seq, we performed multiomics characterization of CAR T cells generated from healthy donor and patients with acute lymphoblastic leukemia.
Highly multiplexed immunohistochemistry (mIHC) enables the staining and quantification of dozens of antigens in a tissue section with single-cell resolution. However, annotating cell populations that differ little in the profiled antigens or for which the antibody panel does not include specific markers is challenging. To overcome this obstacle, we have developed an approach for enriching mIHC images with single-cell RNA sequencing data, building upon recent experimental procedures for augmenting single-cell transcriptomes with concurrent antigen measurements.
View Article and Find Full Text PDFSingle-cell RNA sequencing offers snapshots of whole transcriptomes but obscures the temporal RNA dynamics. Here we present single-cell metabolically labeled new RNA tagging sequencing (scNT-seq), a method for massively parallel analysis of newly transcribed and pre-existing mRNAs from the same cell. This droplet microfluidics-based method enables high-throughput chemical conversion on barcoded beads, efficiently marking newly transcribed mRNAs with T-to-C substitutions.
View Article and Find Full Text PDFLarge-scale cancer genomic studies enable the systematic identification of mutations that lead to the genesis and progression of tumors, uncovering the underlying molecular mechanisms and potential therapies. While some such mutations are recurrently found in many tumors, many others exist solely within a few samples, precluding detection by conventional recurrence-based statistical approaches. Integrated analysis of somatic mutations and RNA expression data across 12 tumor types reveals that mutations of cancer genes are usually accompanied by substantial changes in expression.
View Article and Find Full Text PDFThe anterior pituitary gland drives highly conserved physiologic processes in mammalian species. These hormonally controlled processes are central to somatic growth, pubertal transformation, fertility, lactation, and metabolism. Current cellular models of mammalian anteiror pituitary, largely built on candidate gene based immuno-histochemical and mRNA analyses, suggest that each of the seven hormones synthesized by the pituitary is produced by a specific and exclusive cell lineage.
View Article and Find Full Text PDFPLoS Comput Biol
November 2019
The prevailing paradigm for the analysis of biological data involves comparing groups of replicates from different conditions (e.g. control and treatment) to statistically infer features that discriminate them (e.
View Article and Find Full Text PDFPersonalized medicine is being realized by our ability to measure biological and environmental information about patients. Much of these data are being stored in electronic health records yielding big data that presents challenges for its management and analysis. Here, we review several areas of knowledge that are necessary for next-generation scientists to fully realize the potential of biomedical big data.
View Article and Find Full Text PDFAcute kidney injury (AKI) currently is diagnosed by a temporal trend of a single blood analyte: serum creatinine. This measurement is neither sensitive nor specific to kidney injury or its protean forms. Newer biomarkers, neutrophil gelatinase-associated lipocalin (NGAL, Lipocalin 2, Siderocalin), or kidney injury molecule-1 (KIM-1, Hepatitis A Virus Cellular Receptor 1), accelerate the diagnosis of AKI as well as prospectively distinguish rapidly reversible from prolonged causes of serum creatinine increase.
View Article and Find Full Text PDFTopological methods are emerging as a new set of tools for the analysis of large genomic datasets. They are mathematically grounded methods that extract information from the geometric structure of data. In the last few years, applications to evolutionary biology, cancer genomics, and the analysis of complex diseases have uncovered significant biological results, highlighting their utility for fulfilling some of the current analytic needs of genomics.
View Article and Find Full Text PDFTranscriptional programs control cellular lineage commitment and differentiation during development. Understanding of cell fate has been advanced by studying single-cell RNA-sequencing (RNA-seq) but is limited by the assumptions of current analytic methods regarding the structure of data. We present single-cell topological data analysis (scTDA), an algorithm for topology-based computational analyses to study temporal, unbiased transcriptional regulation.
View Article and Find Full Text PDFPrecision medicine in cancer proposes that genomic characterization of tumors can inform personalized targeted therapies. However, this proposition is complicated by spatial and temporal heterogeneity. Here we study genomic and expression profiles across 127 multisector or longitudinal specimens from 52 individuals with glioblastoma (GBM).
View Article and Find Full Text PDFAmidst the growing literature on cancer genomics and intratumor heterogeneity, essential principles in evolutionary biology recur time and time again. Here we use these principles to guide the reader through major advances in cancer research, highlighting issues of "hit hard, hit early" treatment strategies, drug resistance, and metastasis. We distinguish between two frameworks for understanding heterogeneous tumors, both of which can inform treatment strategies: (1) The tumor as diverse ecosystem, a Darwinian population of sometimes-competing, sometimes-cooperating cells; (2) The tumor as tightly integrated, self-regulating organ, which may hijack developmental signals to restore functional heterogeneity after treatment.
View Article and Find Full Text PDFPLoS Comput Biol
August 2016
The recent explosion of genomic data has underscored the need for interpretable and comprehensive analyses that can capture complex phylogenetic relationships within and across species. Recombination, reassortment and horizontal gene transfer constitute examples of pervasive biological phenomena that cannot be captured by tree-like representations. Starting from hundreds of genomes, we are interested in the reconstruction of potential evolutionary histories leading to the observed data.
View Article and Find Full Text PDFMeiotic recombination is a fundamental evolutionary process driving diversity in eukaryotes. In mammals, recombination is known to occur preferentially at specific genomic regions. Using topological data analysis (TDA), a branch of applied topology that extracts global features from large data sets, we developed an efficient method for mapping recombination at fine scales.
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